The Health Outcome
Breast cancer is the leading cancer among U.S. women. An estimated 192,200 new invasive cases, and an estimated 40,600 deaths, are expected to have occurred during 2001 (1). Ovarian cancer is the sixth most common cancer among U.S. women. An estimated 23,400 new cases, and an estimated 13,900 U.S. deaths are expected to have occurred the same year (1).
Female carriers of germline mutations in the breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) genes have a 40%-60% lifetime risk of developing breast cancer and a 16%-40% risk of developing ovarian cancer (2,3). The incomplete penetrance of the BRCA1/2 gene mutations suggests that other factors, genetic or nongenetic, determine the phenotypic expression of mutant BRCA1/2 alleles in these persons.
The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a possible genetic modifier of BRCA1/2 allele penetrance. Recent evidence of a relationship between the MTHFR gene and ovarian cancer was suggested when allelic deletions of chromosome 1p36.3, a region to which the MTHFR gene maps, were detected in 59% of ovarian tumors (4).
The Finding
To study the putative role the MTHFR gene plays in breast and ovarian tumorigenesis, Gershoni-Baruch et al.(5) determined the frequency of the C677T polymorphism of this gene in Jewish women with breast and/or ovarian cancer. To evaluate gene-gene interaction, these women were also genotyped for the three predominant Jewish BRCA1/2 founder mutations (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 617delT).
The study cohort included 491 women with breast and/or ovarian cancer referred to oncogenetics counseling services at the Sheba and Rambam medical centers in Israel during 1997-1998. Of these, 136 carried BRCA1/2 germline mutations. In addition, 69BRCA1/2 carriers without cancer (healthy individuals at risk, similarly recruited) were included in the study. Data including demographics, histopathological information, treatment, and outcome variables were collected and entered into a computerized database.
Genotyping was performed using DNA extracted from lymphocytes by standard procedures. Mutations were detected by polymerase chain reaction amplification with specific primers that produce a modified restriction enzyme digest made to distinguish the polymorphisms. 491 case subjects were genotyped: 422 had breast cancer, 54 had ovarian cancer, and 15 had both. Of the women who were BRCA1/2 mutation carriers, 95 had breast cancer, 32 had ovarian cancer, and 9 had both.
The same proportion of women with sporadic breast or ovarian cancer (71/355; 20.0%) or a BRCA1/2 mutation (43/205; 21.0%) were MTHFR 677T homozygotes. 677T homozygotes were equally distributed among women diagnosed with breast cancer before (22/122; 18.0%) or after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes who manifested cancer (32/136; 23.5%) or no cancer (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes who developed bilateral breast cancer or both breast and ovarian carcinoma (24/72; 33.3%) was higher than the rate who developed unilateral breast cancer (64/365; 17.5%)(P=0.0026). Differences in morbidity (one versus multiple breast or ovarian tumors) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations.
Public Health Implications
Altered folate metabolism might be implicated in the oncogenic process in both colorectal and ovarian cancers (4,6). The authors concluded that their data, taken together with those reported in the literature, favor the opinion that disruptions in folate metabolism may enhance breast or ovarian tumorigenesis. These results may indicate that breast or ovarian cancer patients homozygous for the 677Tmutation could be at greater risk of acquiring a second primary tumor.
The 677Tmutation results in low MTHFR activity and reduced conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulatory form of folate. Folate deficiency can be circumvented by folic acid supplementation in the diet. 677T homozygosity contributed more to the development of a second primary tumor than did BRCA1/2 carrier status. Thus, the findings reported have potential public health significance for the reduction of second primary tumors among women homozygous for the C677T MTHFR polymorphism. However, it is unclear how generalizable the findings are because the sample is not population based.
References
- Cancer Facts and Figures, 2001. New York: American Cancer Society, 2001.
- Friedman LS, Szabo CI, Ostermeyer EA, et al. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet 1995;57:1284-97.
- Levy-Lahad E, Catane R, Eisenberg S, et al. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: Frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Med Genet 1997;60:1059-67.
- Viel A, Dall’Agnese L, Simone F, et al. Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas. Br J Cancer 1997;75:1105-10.
- Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E. Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 2000;36:2313-6.
- Pereira P, Stanton V, Jothy S, Tomlinson IP, Foulkes WD, Rozen R. Loss of heterozygosity of methlyenetetrahydrofolate reductase in colon carcinomas. Oncol Rep 1999;6:597-9.
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